Congenital heart disorders are the most prevalent lethal birth defects and cardiovascular disease is the leading cause of mortality in adults. A common feature in both pediatric and adult heart disease is altered regulation of cardiac myocyte proliferation, which leads to structural and functional defects in the myocardium. In order to develop well-targeted therapeutic strategies designed to correct heart disease in pediatric or adult patients, the regulatory program directing cardiac myocyte proliferation must be well defined. Vertebrate animal model systems are often used to dissect the molecular mechanisms that regulate developmental and disease processes. However, Ciona intestinalis is an invertebrate animal model system that is well characterized and has many advantages for the study of heart development including: a conserved cardiac gene network, a relatively simple heart design, reduced genetic redundancy, and the ability to study large populations with relative ease in maintenance of the colony. Despite its simplicity, heart development in Ciona is similar to early vertebrate embryos and provides a straightforward avenue for the study of signaling pathways that regulate development, which are extremely complex in higher organisms. A striking difference between mammalian hearts and the Ciona heart is that Ciona are capable of regenerating cardiac myocytes throughout its lifespan, which makes the regulatory mechanisms of cardiac myocyte proliferation in Ciona very intriguing. The signaling mechanisms directing cardiac myocyte proliferation in the Ciona heart have not yet been studied. The goal of this proposal is to determine the signaling mechanisms that regulate cardiac myocyte proliferation and myocardial regeneration in the simple heart of the primitive chordate, Ciona intestinalis. The primary objective is to first determine if transcription factors and signaling molecules known to affect cardiac myocyte proliferation in vertebrates are involved in regulating heart development in Ciona using a transgenic approach. Secondly, the regenerative properties of the Ciona heart will be studied and the signaling mechanisms involved will be identified using modern molecular techniques. Understanding the regulatory mechanisms of cardiac myocyte proliferation and myocardial regeneration in Ciona intestinalis would help simplify the elucidation of the complex regulatory networks directing heart development in humans, which would promote the development of new therapeutic strategies to treat cardiovascular disease. PUBLIC HEALTH RELEVANCE: The proposed research aims to understand the regulatory mechanisms of cardiac myocyte proliferation and myocardial regeneration in the primitive chordate, Ciona intestinalis. The molecular differences between mammalian cardiac myocytes that do not proliferate post-natally and cardiac myocytes in the Ciona heart that are regenerative throughout life are unknown. A complete understanding of cell cycle regulation in cardiac myocytes is necessary before strategies to induce proliferation in these cells can be implemented for patients suffering from cardiac disease. The proposed studies will provide information needed to elucidate the regulatory networks controlling cardiac myocyte proliferation and myocardial regeneration in Ciona, which will have profound implications in the development of well targeted therapeutic strategies and effective drug therapies directed toward the treatment of cardiac disease.